Biology subjects

Roest Crollius, H.

Publications and source records attributed to Roest Crollius, H..

10 recordsLinked to original sources

bioRxiv2022

Evolution is not uniform along protein sequences

Amino acids evolve at different speeds within protein sequences, because their functional and structural roles are different. However, the position of an amino-acid within the sequence is not known to influence this evolutionary speed. Here we discovered that amino-acid evolve almost twice faster at protein termini than in their centre, hinting at a strong topological bias along the sequence length. We further show that the distribution of functional domains and of solvent-accessible residues in proteins readily explain how functional constrains are weaker at their termini, leading to the observed excess of amino-acid substitutions. Finally, we show that methods inferring sites under positive selection are strongly biased towards protein termini, suggesting that they may confound positive selection with weak negative selection. These results suggest that accounting for positional information should improve evolutionary models.

evolutionary biology↗

bioRxiv2022

Genome structures resolve the early diversification of teleost fishes

Accurate species phylogenies are a prerequisite for evolutionary research. Teleosts are by far the largest and the most diversified group of extant vertebrates, but relationships among the three oldest lineages of extant teleosts remain unresolved. Based on seven high-quality new genome assemblies in Elopomorpha (tarpons, eels), we revisited the topology of the deepest branches of the teleost phylogeny using independent gene sequence and chromosomal rearrangement phylogenomic approaches. These analyses converged to a single scenario that unambiguously places the Elopomorpha and Osteoglossomorpha (bony-tongues) in a monophyletic group sister to all other teleosts, i.e., the Clupeocephala lineage. This finding resolves over 50 years of controversy on the evolutionary relationships of these lineages and highlights the power of combining different levels of genome-wide information to solve complex phylogenies. One-Sentence SummaryWhole-genome analyses place Elopomorpha (tarpons, eels) and Osteoglossomorpha (bony-tongues) as sister groups at the deepest branching of crown teleosts.

evolutionary biology↗

bioRxiv2022

A high-resolution comparative atlas across 74 fish genomes illuminates teleost evolution after whole-genome duplication

Teleost fishes are ancient tetraploids stemming from an ancestral whole-genome duplication that may have contributed to the impressive diversification of this clade. Whole-genome duplications can occur via self-doubling (autopolyploidy) or via hybridization between different species (allopolyploidy). The mode of tetraploidization conditions evolutionary processes by which duplicated genomes return to a diploid state through meiosis resolution and subsequent genetic divergence (cytological and genetic rediploidization). How teleosts became tetraploid remains unresolved, leaving a fundamental gap to interpret their functional evolution. As legacy of the whole genome duplication, identifying orthologous and paralogous genomic regions across teleosts is challenging, hindering genome-wide investigations into their polyploid history. Here, we combine tailored gene phylogeny methodology together with a state-of-the-art ancestral karyotype reconstruction to establish the first high-resolution comparative atlas of paleopolyploid regions across 74 teleost genomes. We then leverage this atlas to investigate how rediploidization occurred in teleosts at the genome-wide level. We uncover that some duplicated regions maintained tetraploidy for over 60 million years, with three chromosome pairs diverging genetically only after the separation of major teleost families. This evidence suggests that the teleost ancestor was an autopolyploid. Further, we find evidence for biased gene retention along several duplicated chromosomes, contradicting current paradigms that asymmetrical evolution is specific to allopolyploids. Altogether, our results offer novel insights into genome evolutionary dynamics following ancient polyploidizations in vertebrates.

genomics↗

bioRxiv2021

Classification of non-coding variants with high pathogenic impact

Whole genome sequencing is increasingly used to diagnose medical conditions of genetic origin. While both coding and non-coding DNA variants contribute to a wide range of diseases, most patients who receive a WGS-based diagnosis today harbour a protein-coding mutation. Functional interpretation and prioritization of non-coding variants represents a persistent challenge, and disease-causing non-coding variants remain largely unidentified. Depending on the disease, WGS fails to identify a candidate variant in 20-80% of patients, severely limiting the usefulness of sequencing for personalised medicine. Here we present FINSURF, a machine-learning approach to predict the functional impact of non-coding variants in regulatory regions. FINSURF outperforms state-of-the-art methods, owing to control optimisation during training. In addition to ranking candidate variants, FINSURF also delivers diagnostic information on functional consequences of mutations. We applied FINSURF to a diverse set of 30 diseases with described causative non-coding mutations, and correctly identified the disease-causative non-coding variant within the ten top hits in 22 cases. FINSURF is implemented as an online server to as well as custom browser tracks, and provides a quick and efficient solution to prioritize candidate non-coding variants in realistic clinical settings.

bioinformatics↗

bioRxiv2020

Factors influencing the accuracy in dating single gene trees

Molecular dating is the inference of divergence time from genetic sequences. Knowing the time of appearance of a taxon sets the evolutionary context by connecting it with past ecosystems and species. Knowing the divergence times of gene lineages would provide a context to understand adaptation at the genomic level. However, molecular clock inference faces uncertainty due to the variability of the rate of substitution between species, between genes and between sites within genes. When dating speciations, per-lineage rate variability can be informed by fossil calibrations, and gene-specific rates can be either averaged out or modeled by concatenating multiple genes. By contrast when dating gene-specific events, fossil calibrations only inform about speciation nodes and concatenation does not apply to divergences other than speciations. This study aims at benchmarking the accuracy of molecular dating applied to single gene trees, and identify how it is affected by gene tree characteristics. We analyze 5205 alignments of genes from 21 Primates in which no duplication or loss is observed. We also simulated alignments based on characteristics from Primates under a relaxed clock model, to analyze the dating accuracy. Divergence times were estimated with the bayesian program Beast2. From the empirical dataset, we find that the date estimates deviate more from the median age with shorter alignments, high rate heterogeneity between branches and low average rate, features that underlie the amount of dating information in alignments, hence statistical power. The smallest deviation is associated with core biological functions such as ATP binding, cellular organization and anatomical development, categories that are expected to be under strong negative selection.We then investigated the accuracy of dating with simulated alignments, by controlling the three above parameters separately. It confirmed the factors of precision, but also revealed biases when branch rates are highly heterogeneous. This suggests that in the case of the relaxed uncorrelated molecular clock, biases arise from the tree prior when calibrations are lacking and rate heterogeneity is high. Our study finally reports the scale of the gene tree features that influence the dating consistency with median ages, so that comparisons can be made with other genes and taxa. To tackle the molecular dating of events only observed in single gene trees, like deep coalescence, horizontal gene transfers and gene duplications, future models should overcome the lack of power due to limited information from single genes.

genomics↗

bioRxiv2020

Functional Predictors of Causative Cis-Regulatory Mutations in Mendelian Disease

Undiagnosed neurodevelopmental disease is significantly associated with rare variants in cis-regulatory elements (CRE) but demonstrating causality is challenging as target gene consequences may differ from a causative variant affecting the coding region. Here, we address this challenge by applying a procedure to discriminate likely diagnostic regulatory variants from those of neutral/low-penetrant effect. We identified six rare CRE variants using targeted and whole genome sequencing in 48 unrelated males with apparent X-linked intellectual disability (XLID) but without detectable coding region variants. These variants segregated appropriately in families and altered conserved bases in predicted CRE targeting known XLID genes. Three were unique and three were rare but too common to be plausibly causative for XLID. We compared the cis-regulatory activity of wild-type and mutant alleles in zebrafish embryos using dual-color fluorescent reporters. Two variants showed striking changes: one plausibly causative (FMR1CRE) and the other likely neutral/low-penetrant (TENM1CRE). These variants were "knocked-in" to mice and both altered embryonic neural expression of their target gene. Only Fmr1CRE mice showed disease-relevant behavioral defects. FMR1CRE is plausibly disease-associated resulting in complex misregulation of Fmr1/FMRP rather than loss-of-function. This is consistent both with absence of Fragile X syndrome in the probands and the observed electrophysiological anomalies in the FMR1CRE mouse brain. Although disruption of in vivo patterns of endogenous gene expression in disease-relevant tissues by CRE variants cannot be used as strong evidence for Mendelian disease association, in conjunction with extreme rarity in human populations and with relevant knock-in mouse phenotypes, such variants can become likely pathogenic.

genetics↗

bioRxiv2020

Conserved small nucleotidic elements at the origin of concerted piRNA biogenesis from genes and lncRNAs

PIWI-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing in animal germ cells. The piRNA pathway is increasingly recognized as critical for essential cellular functions such as germline development and reproduction. In the Anopheles gambiae ovary, as much as 11% of piRNAs map to protein-coding genes. Here we show that ovarian mRNAs and long non-coding RNAs (lncRNAs) are processed into piRNAs that can direct other transcripts into the piRNA biogenesis pathway. Targeting piRNAs fuel transcripts either into the ping-pong cycle of piRNA amplification or into the machinery of phased piRNA biogenesis, thereby creating networks of inter-regulating transcripts. RNAs of the same network share related genomic repeats. These repeats give rise to piRNAs, which target other transcripts and lead to a cascade of concerted RNA slicing. While ping-pong networks are based on repeats of several hundred nucleotides, networks that rely on phased piRNA biogenesis operate through short [~]40-nucleotides long repeats, which we named snetDNAs. Interestingly, snetDNAs are recurring in evolution from insects to mammals. Our study brings to light a new type of a conserved regulatory pathway, the snetDNA-pathway, by which short sequences can include independent genes and lncRNAs in the same biological pathway. AUTHOR SUMMARYSmall RNA molecules are essential actors in silencing mobile genetic elements in animal germ cells. The 24-29-nucleotide-long Piwi-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing. Mosquitoes of the Anopheles gambiae species complex are the principal vectors of malaria, and research on their germline is essential to develop new strategies of vector control by acting on reproduction. In the Anopheles gambiae ovary as much as 11% of piRNAs originate from protein-coding genes. We identified piRNAs which are able to target transcripts from several distinct genes or long non-coding RNAs (lncRNAs), bringing together genic transcripts and lncRNAs in a same regulation network. piRNA targeting induces transcript slicing and production of novel piRNAs, which then target other mRNAs and lncRNAs leading again to piRNA processing, thus resulting in a cascade of RNA slicing and piRNA production. Each network relies on piRNAs originating from repeated genetic elements, present in all transcripts of the same network. Some of these repeats are very short, only [~]40-nucleotides long. We identified similar repeats in all 43 animal species that we analysed, including mosquitoes, flies, arachnidae, snail, mouse, rat and human, suggesting that such regulation networks are recurrent, possibly conserved, in evolutionary history.

bioinformatics↗

bioRxiv2020

Synteny-guided resolution of gene trees clarifies the functional impact of whole genome duplications

Whole genome duplications (WGD) have major impacts on the evolution of species, as they produce new gene copies contributing substantially to adaptation, isolation, phenotypic robustness, and evolvability. They result in large, complex gene families with recurrent gene losses in descendant species that sequence-based phylogenetic methods fail to reconstruct accurately. As a result, orthologs and paralogs are difficult to identify reliably in WGD-descended species, which hinders the exploration of functional consequences of WGDs. Here we present SCORPiOs, a novel method to reconstruct gene phylogenies in the context of a known WGD event. WGDs generate large duplicated syntenic regions, which SCORPiOs systematically leverages as a complement to sequence evolution to infer the evolutionary history of genes. We applied SCORPiOs to the 320-million-year-old WGD at the origin of teleost fish. We find that almost one in four teleost gene phylogenies in the Ensembl database (3,391) are inconsistent with their syntenic contexts. For 70% of these gene families (2,387), we were able to propose an improved phylogenetic tree consistent with both the molecular substitution distances and the local syntenic information. We show that these synteny-guided phylogenies are more congruent with the species tree, with sequence evolution and with expected expression conservation patterns than those produced by state-of-the-art methods. Finally, we show that synteny-guided gene trees emphasize contributions of WGD paralogs to evolutionary innovations in the teleost clade.

genomics↗

bioRxiv2018

GC content shapes mRNA decay and storage in human cells

Control of protein expression results from the fine tuning of mRNA synthesis, decay and translation. These processes, which are controlled by a large number of RNA-binding proteins and by localization in RNP granules such as P-bodies, appear often intimately linked although the rules of this interplay are not well understood. In this study, we combined our recent P-body transcriptome with various transcriptomes obtained following silencing of broadly acting mRNA decay and repression factors. This analysis revealed the central role of GC content in mRNA fate, in terms of P-body localization, mRNA translation and mRNA decay. It also rationalized why PBs mRNAs have a strikingly low protein yield. We report too the existence of distinct mRNA decay pathways with preference for AU-rich or GC-rich transcripts. Compared to this impact of the GC content, sequence-specific RBPs and miRNAs appeared to have only modest additional effects on their bulk targets. Altogether, these results lead to an integrated view of post-transcriptional control in human cells where most regulation at the level of translation is dedicated to AU-rich mRNAs, which have a limiting protein yield, whereas regulation at the level of 5 decay applies to GC-rich mRNAs, whose translation is optimal.

molecular biology↗

bioRxiv2018

Genome-wide enhancer - gene regulatory maps in two vertebrate genomes

The spatiotemporal expression of genes is controlled by enhancer sequences that bind transcription factors. Identifying the target genes of enhancers remains difficult because enhancers regulate gene expression over long genomic distances. To address this, we used an evolutionary approach to build two genome-wide maps of enhancer-gene associations in the human and zebrafish genomes. Enhancers were identified using sequence conservation, and linked to their predicted target genes using PEGASUS, a bioinformatics method that relies on evolutionary conservation of synteny. The analysis of these maps revealed that the number of enhancers linked to a gene correlate with its expression breadth. Comparison of both maps identified hundreds of vertebrate ancestral regulatory relationships from which we could determine that enhancer-gene distances scale with genome size despite strong positional conservation. The two maps represent a resource for further studies, including the prioritisation of sequence variants in whole genome sequence of patients affected by genetic diseases.

genomics↗